ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6007-2A>G

dbSNP: rs1555534595
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660091 SCV000782068 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660091 SCV002231913 pathogenic Neurofibromatosis, type 1 2022-02-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 40 (also known as exon 32), but is expected to preserve the integrity of the reading-frame (PMID: 10712197). ClinVar contains an entry for this variant (Variation ID: 547672). Disruption of this splice site has been observed in individual(s) with NF1-related conditions (PMID: 10712197, 15060124, 16786508, 26740943). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 39 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Genome-Nilou Lab RCV000660091 SCV002560170 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002352074 SCV002652214 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-04-26 criteria provided, single submitter clinical testing The c.5944-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 40 in the NF1 gene. This alteration has been identified in individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Upadhyaya M et al. Hum Mutat, 2006 Jul;27:716). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
3billion RCV000660091 SCV003841469 pathogenic Neurofibromatosis, type 1 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000547672). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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